tbuckley/cabot-search huggingface dataset:
OS09.7.A THE ROLE OF MICROSURGERY IN THE FIRST LINE TREATMENT OF VESTIBULAR SCHWANNOMA: IT IS ALL ABOUT THE ODDS
Authors: G Naros, S Wang, K Machetanz, E Weinbrenner, M Tatagiba
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Given the risk for a deterioration of facial function (FDR), first-line (1stline) microsurgery (MS) is discouraged in vestibular schwannoma (VS). In contrast, 1stline radiosurgery (SRS) preserves facial function but has a higher recurrence rate (RR). As salvage VS surgery is very challenging, it could be reasonable to accept a slightly increased FDR of 1stline MS in favor of the lower RR. The aim of the present study was to determine the FDR and RR values of salvage surgery and to calculate the break-even point of MS in the 1stline VS treatment. MATERIAL AND METHODS This retrospective study analyzed all patients with unilateral VS undergoing microsurgery between 03/2008 and 10/2021 (n=1470). We identified patient with 2ndline MS after previous MS (MS-MS) or radiosurgery (SRS-MS) as well as patients with 3rdline MS (MS-SRS-MS). After reviewing patients’ clinical and imaging data, we determined FDR and RR for each cohort. This data was compared to a 1stline MS cohort (CTRL) with a follow-up of at least 10 years (n=572). A mathematical prediction model (MPM) was applied to calculate the odds ratio (OR) of different treatment strategies (i.e., MS-MS, SRS-MS, MS-SRS-MS) depending on different FDR and RR values. RESULTS We identified 48 patients with 2ndline and 11 patients with 3rdline MS after failed MS/SRS. Time to recurrence in relation to the initial treatment was shortest in SRS-MS (35±34 mo) compared to MS-MS (128±179 mo) and MS-SRS-MS (38±17 mo). These patients had a significant worse preoperative facial function than CTRL patients. Extent-of-resection (EOR) was diminished in 2ndline (79% and 75%) compared to 1stline MS (97%). Both the FDR and RR were significantly increased in MS-MS (FDR:17%, RR:14%) and SRS-MS (FDR:45%, RR:5%) compared to CTRL (FDR:12%, RR:4%). Notably, MS-SRS-MS was associated with the highest FDR (60%) while having the lowest GTR rate (54%). MPM indicated that FDR&amp;lt;15% and RR&amp;lt;5% justify a 1stline MS. In the present cohort, these criteria were met for Koos 1-3 tumors (FDR:0-7%, RR:0-3%). CONCLUSION Recurrent VS surgeries fare much worse considering FDR, EOR and RR than first-line surgeries. Hence, reducing the RR of the first-line VS treatment is required. In smaller VS, the surgical oncofunctional outcome can reach the break-even point favoring microsurgery over radiosurgery as first-line treatment option. However, in situations with high FDR (e.g., large or cystic VS) a more conservative surgical approach might be beneficial.
P21.02.B THE EFFECT OF SOCIODEMOGRAPHIC FACTORS ON GLIOMA PROGNOSIS
Authors: M Söderlund, M Sandström, C Almqvist, O Sjöström, A M Dahlin, S Sjöström, B Numan Hellquist, B Melin
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Sociodemographic factors are well known to contribute to health disparities for different cancer diagnoses, but they are not extensively studied for glioma patients. In this study socioeconomic status (SES), travel time to health care, cohabitation status, and region (northern Sweden compared to three regions in southern Sweden) were investigated in relation to prognosis for patients with glioma WHO grade I-IV. MATERIAL AND METHODS The Swedish National Quality Registry for Brain Tumors was used to identify 1276 patients with glioma WHO grade I-IV, diagnosed 2009-2013. The Swedish population-based database RISK North combines data from several health care and demographic registries through the unique personal identity number. The RISK North was used to study survival in relation to SES, cohabitation status (living alone vs living with another adult person), travel time to the closest regional hospital (i.e. the closest hospital with a neurosurgical unit), and region. Educational level was used as a proxy for SES. RESULTS In univariable survival analysis, patients with glioma WHO grade III-IV and high SES had a longer survival compared to patients with low SES (middle school (ref) HR:1, high school HR:0.67 CI[0.56-0.81], university/college HR:0.65 CI[0.53-0.79], p&amp;lt;0.0001). In the multivariable model for the same group, survival was longer for patients with higher SES (middle school (ref) HR:1, high school HR:0.81 CI[0.67-0.98], p=0.033; university/college HR:0.81 CI[0.66-1.00], p=0.048). For patients with glioma WHO grade I-IV, there were no significant differences in survival in relation to travel time, cohabitation status, or region in multivariable survival analysis. CONCLUSION Survival was significantly worse in patients with lower SES compared to higher SES for patients with glioma WHO grade III-IV. No significant differences were found in survival in relation to cohabitation status (between those living alone and those living with another adult person), travel time to regional hospital, or between the northern Sweden and three regions in southern Sweden.
OS07.7.A GLIOBLASTOMA HYBRID CELL STATE CONVEYS RESISTANCE TO CONVENTIONAL THERAPIES
Authors: G Bourmeau, O Anezo, A Ballestin, C Pichol-Thievend, J Reveilles, G Seano
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GB) is a deadly disease and no therapeutic improvements have been made in the last 20 years. High phenotypic plasticity has been recognized as a major obstacle to the efficient treatment of GB. Single-cell sequencing revealed the coexistence of four different cell states within the same tumor. The transition from one subtype (or state) to another, such as from proneural (PN) to mesenchymal (MES), has been suggested as a mechanism for resistance to therapies. However, there is no prognostic value of the current GB states for patients, meaning that mechanisms of resistance may not lie in hardwire identities but in the transition from one subtype to another. Therefore, we investigated the role of the hybrid cell states in GB resistance to therapy. MATERIAL AND METHODS To dynamically follow spatiotemporal changes in GB plasticity in real time, we transduced patient-derived GB cells (patient-derived cell lines with different mutational and phenotypic landscapes) using two specific GB-subtype fluorescent synthetic genetic tracing cassettes. To follow the hybrid cell state dynamics and features, we functionally and transcriptionally investigated GB cells labeled with activated reporters for both the PN and MES subtypes. Using a combination of cytofluorimetry, live imaging, preclinical models, bulk and single-cell RNA-sequencing, we visualized the single-cell GB plasticity and studied the changes in the hybrid state subpopulation proportion over time and under therapeutic stress. RESULTS We discovered that the PN/MES hybrid state (GB-hybrid) has a definite molecular and phenotypic identity and that it is strongly induced after conventional therapies. The GB-hybrid cell state is highly resistant to therapy and more proliferative. Importantly, when implanted in mice the GB-hybrid cells were more aggressive than the rest of the cells, which is consistent with the marked prognostic power for the GB-hybrid geneset signature when tested in the TCGA database. Mechanistically, we showed that GB-hybrid cells were characterized by broad chromatin remodeling, an important increase in overall mRNA quantity per cell and intensification of the nuclear import/export machinery. CONCLUSION Here, we present a novel GB transition cell state between PN and MES subtypes/states. The GB-hybrid is at the same time highly proliferative and resistant to therapy, making it an interesting target to slow down GB recurrence after therapy.
P10.27.A THE INFLUENCE OF DEXAMETHASONE ON TOTAL DNA METHYLATION LEVEL IN GLIOBLASTOMA CELL LINES
Authors: A Barciszewska, A Belter, M Giel-Pietraszuk, I Gawrońska, M Naskręt-Barciszewska
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Dexamethasone (DEX) is a first-line antiedematic drug for glioblastoma (GBM) patients. There is also some evidence it also inhibits GBM cell proliferation and migration, thus impacting patients’ outcomes. However, other studies show that the use of DEX is associated with poor treatment outcomes in GBM patients. The exact mechanism of DEX action is unclear, and no definitive conclusion has yet been reached on its benefits in neurooncological treatment. Temozolomide (TMZ) is a first-line chemotherapeutic in GBM. Epigenetics offers a connection between genetic and environmental factors that influence the development of the disease. The best-characterized epigenetic mark is 5-methylcytosine (m5C) in DNA. The aim of that project is to show the effects of DEX administration on the total DNA methylation level. MATERIAL AND METHODS Using the nucleotide post-labeling method, we analyzed the total amount of m5C in DNA of GBM (T98G, U118, U138), cancer (HeLa) and normal (HaCaT) cell lines treated with DEX, and a combination of DEX and with TMZ. RESULTS We adjusted the DEX doses to the ones achieved in the central nervous system during treatment. We observed dose-dependent increase in total DNA methylation in all cell lines. However, the exposition of GBM cells to the combination of DEX and TMZ caused an adverse synergistic effect resulting in DNA demethylation in high doses of both drugs. In lower concentrations of both drugs DEX kept the increased DNA methylation and attenuated the demethylating effect of TMZ. CONCLUSION Total DNA methylation changes in glioma cell lines under DEX treatment suggest the new mechanism of that drug action and promote clinical implications for adjusting DEX and TMZ therapy in GBM patients. Our results show the potential and possible obstacles of the combined therapy of TMZ with DEX. Our experiments show that combined therapy with both drugs leads to total DNA hypomethylation in high doses of both drugs. Therefore the conclusion would be to adjust DEX administration during TMZ chemotherapy.
P03.06.A FRAMELESS FRACTIONATED STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: AN INSTITUTIONAL SERIES OF 145 CASES
Authors: S S Kilic, A Halima, S T Chao, G Neyman, B Guo, A Magnelli, M D Kolar, Y Cho, P Qi, G H Barnett, L Angelov, A Mohammadi, N M Woody, T Chan, J S Yu, E S Murphy, J H Suh, G H Stevens
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases. MATERIAL AND METHODS In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method. RESULTS 118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There were no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN. CONCLUSION Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.
P22.02.B RELATIVE REPRESENTATIVES IN RESEARCH: HOW TO APPLY PATIENT AND PUBLIC INVOLVEMENT IN THE DEVELOPMENT OF AN INTERVENTION FACILITATING RELATIVE’S INVOLVEMENT IN THE PATIENT’S CARE AND DISEASE TRAJECTORY
Authors: R Guldager, P S Smedegaard, S Nordentoft
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The importance of engaging patients and the public in health research is gaining growing recognition. However, robust evidence of the process seems to be lacking. This study aims to apply Patient and Public Involvement as a panel of relatives from the development to implementation of a clinical tool, to systematically involve relatives of patients with acquired brain injury and a malignant brain tumor in the patient’s care and disease trajectory. MATERIAL AND METHODS This is a descriptive study in the initial phase of applying Patient and Public Involvement in a current research project. Two national patient associations Brain Injury Association and Brain Tumor Association were contacted to recruit relatives of patients within these populations. An informational text with the aim of the overall project and purpose of the research panel was formulated and posted on the home page of- and by the patient associations on behalf of the research group. To enable a broad representation of the whole country, TEAMS was chosen as a communication platform. Preliminary interviews were conducted individually with the relatives and two researchers to align expectations and examine the motivation to participate in the panel. RESULTS Six relatives replied and were considered eligible by the research team, able to express both their own experiences, and representing relatives in general. The relative representatives comprised relatives of patients with acquired brain injury (n=3) and malignant brain tumor (n=3). The relatives were all women between the age of 44 to 66, all partners to the patients, and geographically representing four of the five regions in Denmark. Ethical considerations regarding the relatives were taken into account throughout the process. Two-panel meetings have until now been conducted where the relative representatives have been presented for and discussing findings from two scoping reviews. A pivotal finding is a perceived lack of involvement and systematic support for the children and young adults of the patients. CONCLUSION By including the relatives in the early stage of the research process, they can validate and nuance the research findings by applying their lived experiences and ensuring relevance to a national context. The perspectives and knowledge from the panel are an important foundation before the development of an intervention facilitating the relative’s involvement in the patient’s care and disease trajectory.
P01.07.A HUB-RELATED GRAPH METRICS AS MARKER FOR COGNITIVE OUTCOMES IN ADULT GLIOMA SURVIVORS AFTER MULTIMODAL THERAPY
Authors: L De Roeck, J Blommaert, S Sunaert, P Dupont, P Clement, S De Vleeschouwer, C Sleurs, M Lambrecht
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Although cognitive impairment is a serious and prevalent long-term side effect in adult glioma survivors after therapy, predictive imaging-based markers remain inconsistent to date. Structural brain network topology could be altered by both the tumor and its’ treatment through reorganization of hubs (i.e. highly interconnected nodes). Here, we explored the role of nodal hub-related graph metrics in higher cognitive functioning. MATERIAL AND METHODS 48 WHO grade 2-3 adult glioma survivors (&amp;gt;1 year post-therapy) and 42 matched controls, underwent a cognitive assessment, covering five cognitive domains. Cognitive scores were transformed into w-scores, corrected for age and education. In addition, weighted nodal graph metrics were calculated based on diffusion weighted imaging, using multi-shell multi-tissue constrained spherical deconvolution and anatomically-constrained tractography. Hubs (hub score≥2) were calculated based on 4 nodal metrics, in which the 20% nodes with highest nodal strength and betweenness centrality, and lowest clustering coefficient and characteristic path length received 1 point (score 0-4). Significant differences in nodal graph metrics between patients and controls, and hubs versus non-hubs were tested in a repeated measures ANOVA, using Bonferroni correction for multiple testing. Significant group differences in nodal graph metrics were correlated to cognitive scores per domain. RESULTS In healthy controls 12/78 nodes were defined as hubs, i.e. the bilateral postcentral, precentral, superior frontal, parietofrontal, superior parietal gyri, thalamus and putamen. In glioma survivors, the left superior-parietal region and left putamen had a significantly lower likelihood of being a hub (p&amp;lt;.001). These specific areas showed assortativity to be positively correlated with attention, language and executive function (r(90)&amp;gt;.51, p&amp;lt;.001) and characteristic path length to be negatively correlated with all cognitive domains (r(90)&amp;gt;.51, p&amp;lt;.001). Nodal metrics of clustering coefficient, characteristic path length, local efficiency and assortativity were significantly different between groups in both hub and non-hub regions (both p&amp;lt;.001). Except for betweenness centrality, all nodal metrics strongly correlated with cognitive outcomes, occurring more often in hubs (33-50%) than intermediate hubs (10-33%) or non-hubs (4-12%). CONCLUSION Reorganization of hubs in the brain network is frequently observed in this cohort of glioma survivors compared to healthy controls. Hub connectivity seems to be important in cognitive functioning, more than for non-hub regions. Therefore, structural nodal hub-related graph metrics might be important to consider in predicting cognitive outcomes in glioma survivors.
P11.50.A STEREOTACTIC RADIOSURGERY FOR RECURRENT MEDULLOBLASTOMA IN PEDIATRIC AND ADULT PATIENTS: A SINGLE-INSTITUTION EXPERIENCE
Authors: K H Yoo, N J Marianayagam, D J Park, X Gu, E L Pollom, S G Soltys, S D Chang, A Meola
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic radiosurgery (SRS) emerging as a promising modality for the treatment of recurrent medulloblastoma. Our study aims to provide a comprehensive long-term analysis of the efficacy and safety of SRS for both pediatric and adult patients with recurrent medulloblastomas at a single institution. MATERIAL AND METHODS In our study, we retrospectively reviewed the clinical and radiological records of patients who underwent CyberKnife SRS for medulloblastoma at our institution between 1998 and 2023. Clinical and radiographic follow-up data were available for a total of 15 medulloblastomas in 10 patients. The study population consisted of 8 pediatric patients (ages 3-18) and 2 adult patients (ages 19-75). The median age at the time of SRS was 13 years and the median tumor volume accounted for 1.88 cc. The median biologically equivalent dose (BED) and single-fraction equivalent dose (SFED) were 126 Gy and 18 Gy, respectively. The SRS was administered at the 75% of the median isodose line. RESULTS Following a median follow-up of 39 months (range: 6-78) post-treatment, 8 (53.3%) of the medulloblastomas progressed, 2 (13.3%) showed radiographic regression, and 5 (33.3%) remained stable in volume. The 3-year local tumor control rate for all medulloblastomas was 65.2%, with lower rates observed in the adult cohort (50%) and higher rates in pediatric patients (67.3%). The 3-year overall survival rate was 70%, with significantly higher rates in pediatric patients (75%) compared to adult patients (50%). The 3-year progression-free survival rate was 58.3%, with higher rates in pediatric patients (60%) compared to adult patients (50%). Two pediatric patients developed radiation-induced edema, while two adult patients experienced radiation necrosis at the latest follow-up, with both adult patients passing away. CONCLUSION SRS is a safe and effective long-term treatment option for recurrent medulloblastoma in both pediatric and adult patients, resulting in improved patient outcomes. Although rare, radiation-induced edema and necrosis were observed as adverse events but were manageable. Overall, our findings provide optimistic evidence for the use of SRS as a viable treatment modality for medulloblastoma.
OS13.7.A ONSET SYMPTOMS PREDICT SURVIVAL IN GLIOBLASTOMA PATIENTS -REAL WORLD DATA FROM 1719 PATIENTS IN THE SWEDISH BRAIN TUMOUR REGISTRY 2018-2021
Authors: H Bruhn, L Rosenlund, B Tavelin, R Henriksson
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma, the most common malignant brain tumour in adults, still has a poor long term survival. Non-invasive clinical prognostic markers are important to more accurately predict a patient’s survival. The aim of our register-based real-life study was to explore if onset symptoms have a prognostic value for survival. MATERIAL AND METHODS Data on onset symptoms and survival, as well as known prognostic factors, were retrieved for all glioblastoma patients registered in the Swedish Brain Tumour Registry between 2018 and 2021. The prognostic impact of different onset symptoms were calculated using the Cox proportional hazard model. RESULTS Data from 1719 adults with pathologically verified glioblastoma were analysed. The median survival was 347 days (330-364). The two-year survival was 21.9 %. The most common onset symptoms were focal neurological deficits, cognitive dysfunction, headache, epilepsy, and signs of raised intracranial pressure, with some patients having multiple symptoms. Patients with initial cognitive dysfunction had a significantly shorter survival compared to patients without cognitive dysfunction (p&amp;lt;0.001). Patients with onset seizures had significantly longer survival compared to patients with no onset seizures (p&amp;lt;0.001). The differences in survival remained after Cox regressions adjusting for known prognostic factors. When comparing tumors of the same size, there was still a difference in survival between patients having or not having cognitive dysfunction. CONCLUSION This large real-life study shows that initial cognitive impairment is a negative, and epileptic seizure at onset is a positive prognostic factor for survival in glioblastoma patients.